Steven Attia

Pembrolizumab in advanced soft-tissue sarcoma and bone sarcoma (SARC028): a multicentre, two-cohort, single-arm, open-label, phase 2 trial

BACKGROUNDnPatients with advanced sarcomas have a poor prognosis and few treatment options that improve overall survival. Chemotherapy and targeted therapies offer short-lived disease control. We assessed pembrolizumab, an anti-PD-1 antibody, for safety and activity in patients with advanced soft-tissue sarcoma or bone sarcoma.nnnMETHODSnIn this two-cohort, single-arm, open-label, phase 2 study, we enrolled patients with soft-tissue sarcoma or bone sarcoma from 12 academic centres in the USA that were members of the Sarcoma Alliance for Research through Collaboration (SARC). Patients with soft-tissue sarcoma had to be aged 18 years or older to enrol; patients with bone sarcoma could enrol if they were aged 12 years or older. Patients had histological evidence of metastatic or surgically unresectable locally advanced sarcoma, had received up to three previous lines of systemic anticancer therapy, had at least one measurable lesion according to the Response Evaluation Criteria In Solid Tumors version 1.1, and had at least one lesion accessible for biopsy. All patients were treated with 200 mg intravenous pembrolizumab every 3 weeks. The primary endpoint was investigator-assessed objective response. Patients who received at least one dose of pembrolizumab were included in the safety analysis and patients who progressed or reached at least one scan assessment were included in the activity analysis. Accrual is ongoing in some disease cohorts. This trial is registered with ClinicalTrials.gov, number NCT02301039.nnnFINDINGSnBetween March 13, 2015, and Feb 18, 2016, we enrolled 86 patients, 84 of whom received pembrolizumab (42 in each disease cohort) and 80 of whom were evaluable for response (40 in each disease cohort). Median follow-up was 17·8 months (IQR 12·3-19·3). Seven (18%) of 40 patients with soft-tissue sarcoma had an objective response, including four (40%) of ten patients with undifferentiated pleomorphic sarcoma, two (20%) of ten patients with liposarcoma, and one (10%) of ten patients with synovial sarcoma. No patients with leiomyosarcoma (n=10) had an objective response. Two (5%) of 40 patients with bone sarcoma had an objective response, including one (5%) of 22 patients with osteosarcoma and one (20%) of five patients with chondrosarcoma. None of the 13 patients with Ewings sarcoma had an objective response. The most frequent grade 3 or worse adverse events were anaemia (six [14%]), decreased lymphocyte count (five [12%]), prolonged activated partial thromboplastin time (four [10%]), and decreased platelet count (three [7%]) in the bone sarcoma group, and anaemia, decreased lymphocyte count, and prolonged activated partial thromboplastin time in the soft-tissue sarcoma group (three [7%] each). Nine (11%) patients (five [12%] in the bone sarcoma group and four [10%] in the soft-tissue sarcoma group) had treatment-emergent serious adverse events (SAEs), five of whom had immune-related SAEs, including two with adrenal insufficiency, two with pneumonitis, and one with nephritis.nnnINTERPRETATIONnThe primary endpoint of overall response was not met for either cohort. However, pembrolizumab showed encouraging activity in patients with undifferentiated pleomorphic sarcoma or dedifferentiated liposarcoma. Enrolment to expanded cohorts of those subtypes is ongoing to confirm and characterise the activity of pembrolizumab.nnnFUNDINGnMerck, SARC, Sarcoma Foundation of America, QuadW Foundation, Pittsburgh Cure Sarcoma, and Ewan McGregor.

Doxorubicin plus evofosfamide versus doxorubicin alone in locally advanced, unresectable or metastatic soft-tissue sarcoma (TH CR-406/SARC021): An international, multicentre, open-label, randomised phase 3 trial

BACKGROUNDnEvofosfamide is a hypoxia-activated prodrug of bromo-isophosphoramide mustard. We aimed to assess the benefit of adding evofosfamide to doxorubicin as first-line therapy for advanced soft-tissue sarcomas.nnnMETHODSnWe did this international, open-label, randomised, phase 3, multicentre trial (TH CR-406/SARC021) at 81 academic or community investigational sites in 13 countries. Eligible patients were aged 15 years or older with a diagnosis of an advanced unresectable or metastatic soft-tissue sarcoma, of intermediate or high grade, for which no standard curative therapy was available, an Eastern Cooperative Oncology Group performance status of 0-1, and measurable disease by Response Evaluation Criteria in Solid Tumors version 1.1. Patients were randomly assigned (1:1) to receive doxorubicin alone (75 mg/m2 via bolus injection administered over 5-20 min or continuous intravenous infusion for 6-96 h on day 1 of every 21-day cycle for up to six cycles) or doxorubicin (given via the same dose procedure) plus evofosfamide (300 mg/m2 intravenously for 30-60 min on days 1 and 8 of every 21-day cycle for up to six cycles). After six cycles of treatment, patients in the single-drug doxorubicin group were followed up expectantly whereas patients with stable or responsive disease in the combination group were allowed to continue with evofosfamide monotherapy until documented disease progression. A web-based central randomisation with block sizes of two and four was stratified by extent of disease, doxorubicin administration method, and previous systemic therapy. Patients and investigators were not masked to treatment assignment. The primary endpoint was overall survival, analysed in the intention-to-treat population. Safety analyses were done in all patients who received any amount of study drug. This study was registered with ClinicalTrials.gov, number NCT01440088.nnnFINDINGSnBetween Sept 26, 2011, and Jan 22, 2014, 640 patients were enrolled and randomly assigned to a treatment group (317 to doxorubicin plus evofosfamide and 323 to doxorubicin alone), all of whom were included in the intention-to-treat analysis. The overall survival endpoint was not reached (hazard ratio 1·06, 95% CI 0·88-1·29; p=0·527), with a median overall survival of 18·4 months (95% CI 15·6-22·1) with doxorubicin plus evofosfamide versus 19·0 months (16·2-22·4) with doxorubicin alone. The most common grade 3 or worse adverse events in both groups were haematological, including anaemia (150 [48%] of 313 patients in the doxorubicin plus evofosfamide group vs 65 [21%] of 308 in the doxorubicin group), neutropenia (47 [15%] vs 92 [30%]), febrile neutropenia (57 [18%] vs 34 [11%]), leucopenia (22 [7%] vs 17 [6%]), decreased neutrophil count (31 [10%] vs 41 [13%]), and decreased white blood cell count (39 [13%] vs 33 [11%]). Grade 3-4 thrombocytopenia was more common in the combination group (45 [14%]) than in the doxorubicin alone group (four [1%]), as was grade 3-4 stomatitis (26 [8%] vs seven [2%]). Serious adverse events were reported in 145 (46%) of 313 patients in the combination group and 99 (32%) of 308 in the doxorubicin alone group. Five (2%) patients died from treatment-related causes in the combination group (sepsis [n=2], septic shock [n=1], congestive cardiac failure [n=1], and unknown cause [n=1]) versus one (<1%) patient in the doxorubicin alone group (lactic acidosis [n=1]).nnnINTERPRETATIONnThe addition of evofosfamide to doxorubicin as first-line therapy did not improve overall survival compared with single-drug doxorubicin in patients with locally advanced, unresectable, or metastatic soft-tissue sarcomas and so this combination cannot be recommended in this setting.nnnFUNDINGnThreshold Pharmaceuticals.

Clinical activity of pazopanib in metastatic extraosseous Ewing sarcoma

We report a response to pazopanib in a 69-year-old man with heavily pre-treated metastatic extraosseous Ewing sarcoma in addition to molecular profiling of his tumor. To our knowledge, this case is the earliest to demonstrate activity of an oral multi-targeted kinase inhibitor in Ewing sarcoma. This case provides rationale for adding a Ewing sarcoma arm to SARC024, a phase II study of regorafenib, another multi-targeted kinase inhibitor, in patients with liposarcoma, osteosarcoma and Ewing and Ewing-like sarcomas (NCT02048371). This national multi-institutional study is ongoing.

Follicular Dendritic Cell Sarcoma Presenting As a Thyroid Mass

Case Report A 44-year-old white woman with a history of Hashimoto’s thyroiditis presented to her primary care physician for routine evaluation. A palpable right-sided thyroid nodule was noted. Ultrasound demonstrated heterogeneous enlargement of the thyroid with two 1 cm thyroid nodules (one hypoechoic, one isoechoic) in the lower pole of the right thyroid lobe. A 6-month follow-up ultrasound revealed a hypoechoic nodule measuring 2.7 1.7 2.2 cm (Fig 1A, gold arrow) with peripheral nodularity (Fig 1A, white arrowheads) and Doppler flow (Fig 1B)—all features of malignancy. Fine-needle aspiration suggested anaplastic thyroid carcinoma. The patient underwent a total thyroidectomy, central compartment dissection, and parathyroid reimplantation. Pathology revealed a 2.5 cm extranodal follicular dendritic cell sarcoma (FDCS) (Figs 2A and 2B, inset) in a background of a lymphocytic infiltrate. The tumor was described as high grade due to significant cytological atypia and nuclear pleomorphism. One intrathyroidal parathyroid gland was involved by tumor, as were three of 11 lymph nodes in the central compartment (Fig 2C). Surgical margins of the tumor were negative. Immunostains for CD21 (Fig 2D), CD23 (Fig 2E), vimentin, clusterin (Fig 2F), fascin, podoplanin, and CXCL13 were positive. No features of Castleman’s disease were seen within the tumor specimen or lymph nodes removed. Epstein-Barr virus (EBV) in situ hybridization was negative, as was calcitonin. Adjuvantly, our patient received parotidsparing intensity-modulated radiation therapy (IMRT) to the bilateral neck and tumor bed with 54 Gy. She did not receive adjuvant chemotherapy due to the lack of benefit in reported series. Because of the rarity of the tumor, lack of benefit with known systemic agents, and absence of genomic characterization in the literature, we analyzed the genomic profile of the tumor utilizing the Foundation One genomic analysis developed by the Broad Institute (Cambridge, MA). The assay uses next-generation sequencing to evaluate the status of 236 cancer-related genes.

Validation of a Soft Tissue Sarcoma Nomogram Using a National Cancer Registry.

AbstractBackgroundA nomogram to predict disease-specific mortality (DSM) following surgery for soft tissue sarcoma (STS) has been developed by the Memorial Sloan Kettering Cancer Center (MSKCC). The goal of this study was to validate this nomogram by assessing discrimination and calibration at the population level using a national cancer database.MethodsRetrospective review of the Surveillance, Epidemiology, and End Results cancer registries identified patients undergoing surgery for STS from 1988 to 2011. Data for patient age, tumor size, tumor grade, histologic subtype, sex, primary tumor location, and tumor depth were entered into the nomogram calculator for each patient. Discrimination was quantified using a concordance index. Calibration was assessed by comparing quintiles of nomogram-predicted probabilities of disease-specific mortalityxa0(DSM) with American Joint Committee on Cancer (AJCC) stage DSM.ResultsOverall, 9237 patients were identified with complete information needed for the nomogram. With a mean follow-up of 45xa0months, the concordance index for nomogram-predicted DSM with actual DSM was 0.74 for the entire cohort. For low- and high-grade tumors, this was 0.71 and 0.66, respectively. Kaplan–Meier curves showed better calibration for nomogram-predicted DSM when compared with AJCC staging.ConclusionsOur results validate the use of the MSKCC STS nomogram in the general population, with better predictive ability than AJCC staging. However, a concordance index of 0.74 suggests that further improvement in prognostication is needed, perhaps with biological markers or additional clinical variables.n

Diffuse skeletal muscle metastases from sacral chordoma

Chordomas are rare, slow-growing tumors arising from cellular remnants of the notochord. They account for 1–4xa0% of primary malignant bone tumors and usually occur in the axial skeleton, most commonly the sacrum. Although typically locally recurrent, chordoma metastasis rates as high as 10–42xa0% have been reported. While spread to multiple organ systems has been documented, metastatic disease to skeletal muscle is extremely rare. We present a case of extensive, multifocal skeletal muscle metastases developing in the setting of recurrent sacral chordoma. Our literature search found only one additional case of metastatic chordoma to a single skeletal muscle.

Preoperative radioactive seed localization of nonpalpable soft tissue masses: an established localization technique with a new application

ObjectiveTo describe the technique of iodine125 (I125) seed deployment into nonpalpable soft tissue masses under direct ultrasound (US) or CT guidance for intraoperative localization.Materials and methodsPatients considered candidates for radioactive seed localization (RSL) based on advanced imaging findings underwent an ultrasound examination of the area of concern to verify sonographic visualization of the targeted mass. If the mass was not visible sonographically, CT was used for guidance. Patients were scheduled for surgery 1–4xa0days after seed implantation. Intraoperative frozen section pathological analysis was performed on all patients. Operative time, specimen volume, intraoperative margin status, and final margin status were recorded. Following the surgery, patients and surgeons completed satisfaction surveys.ResultsTen patients underwent seed placement between 1 and 4xa0days prior to surgery. All patients had successful surgical resection of the targeted mass with removal of all implanted radioactive seed(s). There was no seed migration. Intraoperative frozen-section margins were negative (>2xa0mm) in 6/10 patients. Final surgical margins were negative in 9/10 patients. The patient with a positive margin at final pathology did not undergo further resection due to the benign nature of the mass. Patient and surgeon satisfaction survey results were highly positive. All four surgeons reported a strong preference for seed localization over wire localization.ConclusionsRSL is an effective, reliable, and safe technique for preoperative localization of nonpalpable soft tissue masses and yields high patient and surgeon satisfaction.

High-grade endometrial stromal sarcoma as the initial presentation of an adult patient with Peutz-Jeghers Syndrome: a case report

A 46-year-old female presents with a pelvic mass and is diagnosed as having a high-grade endometrial stromal sarcoma. During surgery, she is noted to have areas of intussusception of the small bowel secondary to large hamartomatous polyps. The patient had a previous history of small bowel obstruction secondary to what had been thought to be hyperplastic polyps but represented hamartomatous polyps on further review. Additional examination revealed the presence of subtle hyperpigmented macules on the fingers leading to a diagnosis of Peutz-Jeghers Syndrome (PJS). The diagnosis was confirmed by the presence of a germ-line STK11 mutation. Immunohistochemistry analysis of the tumor showed decreased expression of STK-11 as compared to one of the patient’s hamartomatous polyps. Next generation sequencing of the tumor specimen failed to demonstrate a “second hit” somatic mutation in STK-11. This case represents the first case of endometrial stromal sarcoma associated with PJS and illustrates the importance of increased awareness of this condition among oncologists. PJS is associated with dysregulation of the mTOR pathway; treatment with an mTOR inhibitor was not effective in this case.

Association between programmed death-Ligand 1 expression and the vascular endothelial growth factor pathway in angiosarcoma

Angiosarcoma is a vascular malignancy associated with a poor prognosis and chemotherapy resistance. The tumor immune microenvironment of angiosarcoma has not been characterized. We investigated the expression of programmed death-ligand 1 (PD-L1) and programmed death 1 (PD-1) in angiosarcoma and correlated these findings with vascular endothelial growth factor (VEGF)-related gene expression and survival. Using archived formalin-fixed paraffin-embedded tissues of primary and metastatic angiosarcoma specimens, we characterized the immunohistochemical (IHC) expression of PD-L1 and PD-1. In addition, we extracted RNA from each tumor and quantified the expression of VEGF-related genes, and then tested if these genes were associated with PD-L1 and PD-1 expression and clinical outcomes. Retrospective review identified 27 angiosarcoma specimens collected between 1994 and 2012. IHC expression of tumor PD-L1, tumor-infiltrating immune cell PD-L1, and tumor-infiltrating immune cell PD-1 expression was identified in 5 (19%), 9 (33%), and 1 (4%) specimens, respectively. Expression of PD-L1 and PD-1 was not associated with VEGF-related gene expression or survival. PD-L1 tumor and tumor-infiltrating immune cells expression was identified in a large proportion of patients. Though neither was associated with VEGF-related gene expression or prognosis, targeting PD-1/PD-L1 may be of benefit for a significant proportion of angiosarcomas that do not respond to surgery, chemotherapy, or radiation.

Abstract B237: CD105: A therapeutic target for sarcomas.

Purpose: Endoglin/CD105 is a homodimeric transmembrane glycoprotein that is expressed on the proliferating endothelium of solid tumors. TRC105, the chimeric IgG1 antibody with high affinity binding for human CD105, has recently undergone human testing. This exploratory study sought to validate CD105 as a potential therapeutic target in sarcomas. Methods: We performed immunohistochemical staining for CD105 expression in 146 retrospectively identified paraffin embedded sarcoma patient samples in our tumor registry, utilizing an anti-CD105 antibody (clone 4G11, Novocastra). The diagnoses were verified and samples were examined for CD105 expression in the malignant vasculature as well as tumor cells. Results: The vast majority of specimen expressed CD105 in the tumor vasculature, 134 of 137 evaluable cases. CD105 expression in the cells of the varied sarcoma histologies themselves were as follows: 19/20 angiosarcomas, 6/7 Ewing sarcomas, 8/20 undifferentiated pleomorphic sarcomas, 6/20 uterine leiomyosarcomas (LMS), 4/20 osteosarcomas, 3/20 non-uterine LMS, 3/20 synovial sarcomas. None of the 19 evaluated chondrosarcoma cells expressed CD105. Thirteen of 19 angiosarcomas showed CD105 expression in >50% of tumor cells, 3 of 19 showed CD105 expression in 25-49% of the tumor cells and 3 of 19 showed CD105 expression in 5-24% of tumor cells. Conclusions: CD105 targeting appears to be a rational antiangiogenic therapeutic approach in sarcomas, with particular emphasis on angiosarcomas. A clinical trial utilizing TRC105 in soft tissue sarcomas is currently under development. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B237. Citation Format: Karen Fritchie, Steven Attia, Scott Okuno, Carola Arndt, Steven Robinson. CD105: A therapeutic target for sarcomas. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B237.